Proteinases from polymorphonuclear leukocytes and macrophages, especially elastases (human leukocyte elastase and cathepsin G), appear to be responsible for the chronic tissue destruction associated with inflammation, arthritis and emphysema. During infection or inflammation, the normal lung is protected from proteolytic digestion by the protease inhibitor, .alpha..sub.1 -antitrypsin. The protective mechanism appears to be nonoperative in individuals with an .alpha..sub.1 -antitrypsin deficiency due to genetic or other causes. Synthetic elastase inhibitors capable of replacing .alpha..sub.1 -antitrypsin therefore appear to be useful in the treatment of pulmonary emphysema and related diseases.
Several types of elastase inhibitors have been reported in the literature. These include peptide chloromethyl ketones as described in "Inhibition of Human Leukocyte Elastase by Peptide Chloromethyl Ketones", P. M. Tuhy and J. C. Powers, FEBS Letters, 50, 359-61 (1975); "Specificity of Porcine Pancreatic Elastase, Human Leukocyte Elastase and Cathepsin G. Inhibition with Peptide Chloromethyl Ketones", J. C. Powers, B. F. Gupton, A. D. Harley, N. Nishino and R. J. Whitley, Biochem. Biophys. Acta. 485, 156-66 (1977); azapeptides "Proteinase Inhibitors. 1. Inhibitors of Elastase", C. P. Dorn, M. Zimmerman, S. S. Yang, E. C. Yurewicz, B. M. Ashe, R. Frankshun and H. Jones, J. Med. Chem., 20, 1464-68 (1977); "Reaction of Serine Proteases with Aza-amino Acid and Aza-peptide Derivatives", J. C. Powers and B. F. Gupton, Meth. Enzymol., 46, 208-16 (1977); sulfonyl fluorides "Specificity and Reactivity of Human Leukocyte Elastase, Porcine Pancreatic Elastase, Human Granulocyte Cathepsin G, and Bovine Pancreatic Elastase, Human Granulocyte Cathepsin G, and Bovine Pancreatic Chymotrypsin with Arylsulfonyl Fluorides. Discovery of a new series of potent and specific irreversible Elastase Inhibitors", T. Yoshimura, L. N. Barker and J. C. Powers, J. Biol. Chem., 257, 5077-84 (1982); heterocyclic acrylating agents "Inhibition of Elastase and Other Serine Proteases by Heterocyclic Acylating Agents", M. Zimmerman, H. Morman, D. Mulvey, H. Jones, R. Frankshun and B. M. Ashe, J. Biol. Chem., 255, 9848-51 (1980); "Selective Inhibition of Human Leukocyte Elastase and Bovine .alpha..sub.1 -Chymotrypsin by Novel Heterocycles", B. M. Ashe, R. L. Clark, H. Jones and M. Zimmerman, J. Biol. Chem., 256: 11603-6 (1981); imidazole N-carboxamides, W. C. Groutas, R. C. Badger, T. D. Ocain, D. Felker, J. Frankson and M. Theodorakis, Biochem. Biophys. Res. Commun., 95, 1890 (1980); and p-nitrophenyl-N alkyl carbamates, "p-Nitrophenyl Carbamates as Active-Site-Specific Reagents for Serine Proteases", R. E. Scofield, R. P. Werner and F. Wold, Biochemistry, 16, 2492 (1977).
Although some peptide chloromethyl ketones have been shown to be effective in preventing elastase induced emphysema in animal models "Prevention of Elastase Induced Experimental Emphysema by Oral Administration of a Synthetic Elastase Inhibitor,", A. Janoff and R. Dearing, Am. J. Respir. Dis., 121, 1025-3 (1980), there is considerable question whether such reactive agents could be used for treating emphysema in humans. This is not surprising since the alkylating moieties in these inhibitors might render them toxic when used on a continuous basis. To be suitable for human use, an enzyme inhibitor has to show a high degree of selectively and must have minimal toxic side effects. As a result, most drugs are molecules that reversibly bind to specific enzymes or receptor sites. Examples are the carbamate esters physostigmine and neostigmine which have been clinically used as inhibitors of acetyl choline esterases, A. G. Gilman, L. S. Goodman, and A. Gilman, "The pharmacological Basis of Therapeutics", p. 101, MacMillan Publishing Co. (1980).
There accordingly remains a need in the art for compounds which are specific and active-site directed inhibitors of the enzyme elastase which are not subject to the disadvantages of compounds known in the art for this purpose.